Fluticasone furoate in the treatment of copd

ABSTRACT

The present invention relates to a method of reducing the rate of decline in lung function in a human patient with COPD, wherein the human patient having COPD has a blood eosinophil count of ≥150 cells/μL, and further wherein the method comprises administering to the patient an inhaled pharmaceutical product comprising fluticasone furoate.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pharmaceutical products comprisingfluticasone furoate for use in the treatment of COPD patients,particularly a subgroup of COPD patients that possess a blood eosinophilcount of, for example, ≥150 cells/μl. The present invention is furtherdirected to methods for treating a patient with COPD which methodincludes identifying a patient that will respond to treatment andadministering a pharmaceutical product of the present inventioncomprising fluticasone furoate to said patient.

BACKGROUND TO THE INVENTION

Chronic Obstructive Pulmonary Disease (COPD), a leading cause ofmorbidity and mortality worldwide, is characterised by persistentairflow limitation that is typically progressive and associated with anenhanced chronic inflammatory response in the airways to noxiousparticles or gases. Symptoms of COPD include dyspnea, chronic cough orthe production of sputum and spirometry analysis is typically requiredto confirm diagnosis. A post-bronchodilator FEV₁/FVC<0.70 confirms thepresence of airflow limitation and thus COPD. A number of factors havebeen identified that influence the development and progression of COPD,the most studied of which is smoking tobacco cigarettes. Other factorsinclude for example infection, genetics and exposure to particles, suchas occupational dusts, chemical agents and pollution from heating fuels.

COPD can be mild to very severe and assessment of the disease isnecessary for administration of the appropriate medication to controland/or relieve symptoms. An assessment of a patient's symptoms mayinclude, for example, the COPD Assessment Test (CAT), the COPD ControlQuestionnaire (CCQ), the St. George's Respiratory Questionnaire (SGRQ)test, Forced Expiratory Volume (FEV₁) analysis, and an assessment oftheir exacerbation risk.

A number of medications are available for the treatment of COPD andthese are used mainly to reduce symptoms and reduce the frequency andseverity of exacerbations and can include bronchodilators, such asbeta₂-agonists and anticholinergics, corticosteroids (oral and inhaled),PDE-4 inhibitors, methylxanthines and combinations of some of the above.Bronchodilator medications are vital to symptom management in COPD andthe choice between monotherapy with a beta₂-agonist, anticholinergic ortheophylline, or combination therapy is dependent upon how effective themedication controls a patient's symptoms.

According to the 2014 Global Initiative for Chronic Obstructive LungDisease (GOLD) strategy, for a patient with few to more significantsymptoms but a low risk of exacerbations, bronchodilators are therecommended initial therapy (short-acting if the patient has fewsymptoms and long-acting if the patient has more pronounced symptoms).For COPD patients with a high risk of exacerbations, inhaledcorticosteroids are recommended in combination with a beta₂-agonist oranticholinergic.

WO2011/067212/US 2012-309725 describes the combination of the muscarinicantagonist umeclidinium bromide with the beta₂-agonist vilanteroltrifenatate, which has recently been approved in the US for thetreatment of COPD. WO2011/067212 further describes the triplecombination therapy of umeclidinium bromide, vilanterol trifenatate andfluticasone furoate for use in the treatment of COPD.

There is also interest in personalised medicine in COPD through theidentification of biomarkers that can be used to select a particularpopulation of COPD patients that will derive most benefit from apharmacologic treatment. For example, studies have shown that COPDpatients with different levels of eosinophils in induced sputum andblood can respond differently to certain corticosteroids (Brightling etal, Lancet 2000; 356: 1480-85; Pizzichini et al, Am J Respir Crit CareMed, Vol 158. Pp-1511-1517, 1998; Kitaguchi et al, International Journalof COPD 2012: 7, 283-289). Greater improvements were observed inpatients who had higher eosinophil counts compared to patients withlower counts.

Studies have further investigated whether sputum and blood eosinophilcounts can be used to direct corticosteroid treatment of exacerbationsin COPD (Bafadhel et al, Am J Respir Crit care Med, Vol 186, Iss. 1, pp48-55, Jul. 1, 2012; Siva et al, Eur Respir J 2007; 29: 906-913).

Despite the research that has been performed in this area to date, thereexists a need for further, improved therapies for use in the treatmentof COPD patients with a certain level of eosinophils in the lungs.

Furthermore, studies to date that have investigated the benefit ofcorticosteroid treatment in COPD patients with high and low eosinophilcounts have assessed short-term effects such as improvement in FEV₁ orreduction in the frequency of exacerbations. No studies appear toinvestigate or discuss whether corticosteroid therapy can have an impacton lung function decline, the hallmark of the disease, in asubpopulation of COPD patients with a certain eosinophil count. In fact,the GOLD strategy states that, for COPD patients generally, prescriptionmedicines are used to reduce symptoms, reduce frequency and severity ofexacerbations, and improve health status and exercise tolerance, butthat none of the existing treatments have been shown conclusively inclinical studies to modify the long-term decline in lung function thatis characteristic of the disease.

Thus, there is a further need for therapies for use in the treatment ofCOPD in individual members of the subpopulation of COPD patients,wherein those therapies are able to reduce the rate of decline in lungfunction.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical products comprisingfluticasone furoate for use in the treatment of COPD patients,particularly individual members of a subgroup of COPD patients thatthrough analysis have been identified as possessing an eosinophil bloodcount of ≥150 cells/μl.

In one embodiment, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in the treatment of COPDin a patient, wherein the patient has a blood eosinophil count of ≥150cells/μl, wherein the pharmaceutical product reduces the rate of declinein lung function in a COPD patient.

The present invention is further directed to methods for treating apatient with COPD which methods include identifying a patient that willrespond to treatment and administering a pharmaceutical product of thepresent invention comprising fluticasone furoate to said patient.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “fluticasone furoate” refers to6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, an inhaled corticosteroidthat has been shown in clinical studies to be well-tolerated andsuitable for once-daily administration in the treatment of asthma andCOPD. Fluticasone furoate in combination with vilanterol trifenatate hasrecently been approved for the once-daily treatment of COPD in the USand asthma and COPD in Europe. Fluticasone furoate is described inWO02/12265/U.S. Pat. No. 7,101,866, which is incorporated by referenceherein. Fluticasone furoate may be abbreviated to “FF”.

As used herein, the term “lung function” refers to a COPD patient'sforced expiratory volume in 1 second (FEV₁). FEV₁ is the volume of airexhaled during the first second of maximal forced expiration startingfrom a position of full inspiration. Lung function in healthy personsdeclines as a result of the natural aging process. In COPD patients,lung function declines at an accelerated rate. Decline in lung functionmay be measured in terms of millilitres per year (ml/year). Thepharmaceutical products of the present invention comprising fluticasonefuroate are intended to reduce the rate of decline in lung function in apatient with COPD, when compared to the same product without fluticasonefuroate. Use of the phrase “reduces the rate of decline in lungfunction” herein in connection with a pharmaceutical product of thepresent invention comprising fluticasone furoate, refers to that productresulting in a smaller decline in FEV₁ over a defined period, forexample 1 year, than the same product excluding fluticasone furoate (i.ethe inhaled corticosteroid component). For example, if administration ofa pharmaceutical product consisting of fluticasone furoate resulted inan FEV₁ decline of 20 ml/year and administration of placebo resulted inan FEV₁ decline of 45 ml/year, the pharmaceutical product comprising theinhaled corticosteroid (fluticasone furoate) will have reduced the rateof decline by 25 ml/year. In a further example, if administration of apharmaceutical product comprising of fluticasone furoate andumeclidinium bromide resulted in an FEV₁ decline of 30 ml/year andadministration of a pharmaceutical product consisting of umeclidiniumbromide (i.e. same pharmaceutical product but without the corticosteroidcomponent) resulted in an FEV₁ decline of 65 ml/year, the pharmaceuticalproduct comprising the inhaled corticosteroid (fluticasone furoate) willhave reduced the rate of decline by 35 ml/year.

In one embodiment, a pharmaceutical product of the invention reduces therate of decline in lung function by between 10 to 19 ml/year, 20 to 29ml/year, 30 to 39 ml/year, 40 to 49 ml/year, 50 to 59 ml/year, 60 to 69ml/year, 70 to 79 ml/year, 80 to 89 ml/year, 90 to 99 ml/year, 100 to109 ml/year, 110 to 119 ml/year, 120 to 129 ml/year, 130 to 139 ml/year,140 to 149 ml/year, 150 to 159 ml/year, 160 to 169 ml/year, 170 to 179ml/year, 180 to 189 ml/year or 190 to 199 ml/year. In one embodiment, apharmaceutical product of the invention reduces the rate of decline inlung function by greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45,50, 55, 60, 70, 80, 90, 100, 125, 150, 175 or 200 ml/year.

As used herein, the term “blood eosinophil count” may refer to thenumber of eosinophils per microlitre (cells/p1) of blood. In oneembodiment, the blood eosinophil count in a patient with COPD treatedwith a pharmaceutical product of the present invention is greater than150 eosinophils/μl, for example, greater than 175/μl, 200 μl, 225 μl250/μl, 275 μl, 300 μl, 350/μl, 450/μl, 500/μl, 750/μl or 1000/μl. COPDpatients with a blood eosinophil count greater than, for example 75,100, 125 cells/μl may also derive greater benefit from treatment with apharmaceutical product of the present invention compared to patientswith a blood eosinophil count below the selected level. The bloodeosinophil count may also be expressed as the percentage of white bloodcells, also known as leukocytes, in a blood sample that are eosinophils.The blood eosinophil count may be, for example, greater than 2%, 2.5%,3%, 3.5% or 4%. In one embodiment, the blood eosinophil count in apatient with COPD treated with a pharmaceutical product of the presentinvention is greater than 2%. The blood eosinophil count can be manuallyor automatically calculated by methods well known in the art. Typically,a sample of blood is taken from a peripheral vein and analysed by aninstrument (e.g. Automated Analyser) that provides the total number ofwhite blood cells. All the white blood cell types can be provided as anabsolute number per litre or percentage. A complete blood count withdifferential count also provides how many cells are eosinophils as anabsolute value (cells/L or cells/μl of blood) or percentage of totalwhite blood cells.

It will be appreciated by those skilled in the art that a bloodeosinophil count calculated as a percentage can be converted to aneosinophil/μl value and vica versa. Moreover, either expression of theeosinophil count can be calculated and/or referred to as part of theuses and methods of the present invention.

In one aspect, a COPD patient's blood eosinophil count is calculatedfrom the analysis of a single blood sample. In another aspect, a COPDpatient's blood eosinophil count is an average value calculated from theanalysis of multiple blood samples (e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10)taken over a period of time (e.g. one week or one-month).

As used herein, the term “pharmaceutical product” means the medicamentthat is used by the patient for the treatment of COPD. The term includesany device, such as an inhaler, or devices, that is/are required fordelivery of the composition or compositions contained within thatinclude the active therapeutic agents. A pharmaceutical product of thepresent invention comprising fluticasone furoate and optionally one ormore therapeutic agents, may be any product that is capable ofdelivering the therapeutic agent(s) by the inhaled route. Furthermore,the pharmaceutical product may be more than one inhaler where, forexample, the pharmaceutical product comprises two or more therapeuticagents and these are presented as separate compositions in differentinhalers but intended to be used in combination for the treatment ofCOPD. A pharmaceutical product that contains two or more therapeuticagents can, however, be a single inhaler, wherein the two or moretherapeutic agents are formulated in the same composition or presentedin separate compositions within the same inhaler.

As used herein, the term “responder” refers to a COPD patient whothrough analysis has been identified as someone who will benefit fromtreatment with a pharmaceutical product of the present invention. Aresponder will also have a greater response to and derive greaterbenefit from treatment than a COPD patient who has been identified as a“non-responder”. In the context of the present invention, a responder isa COPD patient who has a blood eosinophil count of ≥150 cells/μl or >2%,determined by analysis of a peripheral blood sample.

As used herein, the term “umeclidinium bromide” refers to4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide, the long acting high-affinity pan-active muscarinic receptorantagonist which has potential for once-daily administration.Umeclidinium bromide in combination with vilanterol trifenatate has beenapproved in the US for the treatment of COPD. Umeclidinium bromide maybe prepared as described in WO2005/104745/U.S. Pat. No. 7,488,827(Example 84) or WO2014/027045, which are incorporated herein byreference. Umeclidinium bromide may be abbreviated to “UMEC”.

As used herein, the term “vilanterol trifenatate” refers to4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenoltriphenylacetate, the long-acting beta₂-agonist that provides sustainedbronchodilation over a period of 24 hours or more and is suitable foronce-daily administration. Vilanterol trifenatate may be prepared asdescribed in WO2003/024439 (Example 78(i))/US RE44874, which isincorporated herein by reference. Vilanterol trifenatate may beabbreviated to “VI”.

The present invention is directed to pharmaceutical products comprisingfluticasone furoate for use in the treatment of a subgroup of COPDpatients. A subgroup of COPD patients of interest for the presentinvention are those have a blood eosinophil count ≥150 cells/μl sincethese patients may show an improved clinical response to treatment witha pharmaceutical product of the invention, compared to patients with ablood eosinophil count <150 cells/μl.

It will be appreciated by those skilled in the art that a patient'seosinophil count may alternatively be calculated or determined byanalysis of an induced sputum sample rather than a blood sample.Therefore, the present invention is also directed to methods of treatingCOPD wherein instead of including a step directed to the calculation ofa blood eosinophil count said method includes a step directed to thecalculation of a sputum eosinophil count. Moreover, the presentinvention is also directed to uses of a pharmaceutical productcomprising fluticasone furoate for the treatment of COPD, wherein theuse refers to the patient having a sputum eosinophil count, forexample >2%, rather than a blood eosinophil count.

COPD patients who have blood eosinophil count of for example ≥150cell/μl or >2% may derive more benefit from treatment with an inhaledcorticosteroid than those COPD patients that have lower levels ofeosinophils. COPD patients with these higher levels of eosinophilstreated with fluticasone furoate may, when compared with placebo, haveimproved FEV₁, improved Quality of Life (QoL) or health statusdetermined by the CRQ or the SGRQ, improved dyspnea or a reduction inexacerbation frequency and severity.

Eosinophil level, for example blood eosinophil count, in stable COPD maypredict the likely magnitude of the benefit of inhaled corticosteroidtherapy, such as fluticasone furoate, in reducing the rate of moderateand/or severe COPD exacerbations. COPD patients with raised bloodeosinophils may also have a greater risk of exacerbations. COPD patientswith these higher levels of eosinophils treated with fluticasone furoatemay, when compared with placebo or the same product absent the inhaledcorticosteroid component, experience a reduction in COPD exacerbationfrequency and/or severity.

In a first aspect, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in the treatment of COPDin a patient, wherein the patient has a blood eosinophil count of ≥150cells/μl.

In another aspect, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in a method of treatingCOPD in a patient, wherein the patient has a blood eosinophil count of≥150 cells/μl, and wherein the method comprises identifying that thepatient has a blood eosinophil count of ≥150 cells/μl by analysis of ablood sample taken from said patient and then administering thepharmaceutical product comprising fluticasone furoate to the patient.

In a further aspect, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use in thetreatment of COPD in a patient classified as a responder using a methodcomprising:

-   -   a. calculating the number of eosinophils per microlitre of blood        in a blood sample taken from a COPD patient;    -   b. determining that the patient is a responder if the number of        eosinophils in the blood sample is ≥150 cells/μl.

In a further aspect, the present invention is directed to a method oftreating COPD in a patient comprising the steps of:

-   -   a. calculating the eosinophils per microlitre (μl) of blood in a        blood sample taken from a COPD patient;    -   b. determining that the patient is a responder if the number of        eosinophils in the blood sample is ≥150 cells/μl;    -   c. administering a therapeutically effective amount of a        pharmaceutical product comprising fluticasone furoate to said        patient identified as a responder.

In a further aspect, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forthe treatment of COPD in a patient, wherein the patient has a bloodeosinophil count of ≥150 cells/μl.

In a further aspect, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product foruse in a method of treating COPD in a patient, wherein the patient has ablood eosinophil count of ≥150 cells/μl, and wherein the methodcomprises identifying that the patient has a blood eosinophil count of≥150 cells/μl by analysis of a blood sample taken from said patient andthen administering the pharmaceutical product comprising fluticasonefuroate to the patient.

In a first aspect, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in the treatment of COPDin a patient, wherein the patient has a blood eosinophil count of >2%.

In another aspect, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in a method of treatingCOPD in a patient, wherein the patient has a blood eosinophil count >2%,and wherein the method comprises identifying that the patient has ablood eosinophil count >2% by analysis of a blood sample taken from saidpatient and then administering the pharmaceutical product comprisingfluticasone furoate to the patient.

In a further aspect, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use in thetreatment of COPD in a patient classified as a responder using a methodcomprising:

-   -   a. calculating the percentage (%) of eosinophils in a blood        sample taken from a COPD patient;    -   b. determining that the patient is a responder if the percentage        of eosinophils in the blood sample is >2%.

In a further aspect, the present invention is directed to a method oftreating COPD in a patient comprising the steps of:

-   -   a. calculating the percentage (%) of eosinophils in a blood        sample taken from a COPD patient;    -   b. determining that the patient is a responder if the percentage        of eosinophils in the blood sample is >2%;    -   c. administering a therapeutically effective amount of a        pharmaceutical product comprising fluticasone furoate to said        patient identified as a responder.

In a further aspect, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forthe treatment of COPD in a patient, wherein the patient has a bloodeosinophil count of >2%.

In a further aspect, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product foruse in a method of treating COPD in a patient, wherein the patient has ablood eosinophil count >2%, and wherein the method comprises identifyingthat the patient has a blood eosinophil count >2% by analysis of a bloodsample taken from said patient and then administering the pharmaceuticalproduct comprising fluticasone furoate to the patient.

The present invention is directed to pharmaceutical products for thetreatment of COPD. COPD is a chronic disease characterised by persistentairflow limitation that manifests as daily symptoms, such as dyspnea,chronic cough and a limitation in the patient's ability to perform dailyactivities. Chronic airflow limitation is caused by a mixture of smallairways disease (obstructive bronchiolitis) and parenchymal destruction(emphysema). Furthermore, exacerbations of respiratory symptoms oftenoccur in patients with COPD, triggered by a number of factors such asbacteria, virus and environmental pollutants. The GOLD strategy for thediagnosis, management and prevention of COPD (2014) states that once apatient has been diagnosed with COPD, there are two goals underpinningtheir treatment. The first goal is to reduce the patient's symptoms,i.e. relieve symptoms, improve health status and improve tolerance toexercise. The second goal is to reduce the patient's risk, meaningaltering the progression of the disease, preventing and reducingseverity of exacerbations or reducing mortality. The GOLD strategystates that prescription medicines are used to reduce symptoms, reducefrequency and severity of exacerbations and improve health status andexercise tolerance but that none of the existing treatments have beenshown conclusively in clinical studies to modify the long-term declinein lung function that is characteristic of the disease. For example, oneof the existing medicaments available is inhaled corticosteroids and theGOLD strategy states that various studies investigating the use ofinhaled corticosteroids in the treatment of COPD have shown that“regular treatment with inhaled corticosteroids does not modify thelong-term decline in FEV₁ nor mortality in patients with COPD”.

There is, consequently, a need for further pharmacologic therapies thatare able to modify the long-term decline in lung function seen in COPDpatients, or a subgroup of COPD patients, and thus slow their diseaseprogression.

The present invention provides such a therapy. In one embodiment, thepresent invention is directed to a pharmaceutical product comprisingfluticasone furoate for use in the treatment of COPD in a patient,wherein the patient has a blood eosinophil count of ≥150 cells/μl,wherein the pharmaceutical product reduces the rate of decline in lungfunction in a COPD patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use in amethod for reducing the rate of decline in lung function COPD in apatient, wherein the patient has a blood eosinophil count of ≥150cells/μl, and wherein the method comprises identifying that the patienthas a blood eosinophil count of ≥150 cells/μl by analysis of a bloodsample taken from said patient and then administering the pharmaceuticalproduct comprising fluticasone furoate to the patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use inreducing the rate of decline in lung function in a COPD patientclassified as a responder using a method comprising:

a. calculating the number of eosinophils per microlitre (μl) of blood ina blood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl.

In a further embodiment, the present invention is directed to a methodof reducing the rate of decline in lung function in a patient with COPDcomprising the steps of:

a. calculating the number of eosinophils per microlitre (μl) of blood ina blood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl;

c. administering a therapeutically effective amount of a pharmaceuticalproduct comprising fluticasone furoate to said patient identified as aresponder.

In a further embodiment, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forreducing the rate of decline in lung function in a patient with COPD,wherein the patient has a blood eosinophil count of ≥150 cells/μl.

In a further embodiment, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forreducing the rate of decline in lung function in a patient with COPD,wherein the patient has a blood eosinophil count of ≥150 cells/μl, andwherein the method comprises identifying that the patient has a bloodeosinophil count of ≥150 cells/μl by analysis of a blood sample takenfrom said patient and then administering the pharmaceutical productcomprising fluticasone furoate to the patient.

In one embodiment, the present invention is directed to a pharmaceuticalproduct comprising fluticasone furoate for use in the treatment of COPDin a patient, wherein the patient has a blood eosinophil count of >2%,wherein the pharmaceutical product reduces the rate of decline in lungfunction in a COPD patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use in amethod for reducing the rate of decline in lung function COPD in apatient, wherein the patient has a blood eosinophil count >2%, andwherein the method comprises identifying that the patient has a bloodeosinophil count >2% by analysis of a blood sample taken from saidpatient and then administering the pharmaceutical product comprisingfluticasone furoate to the patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate for use inreducing the rate of decline in lung function in a COPD patientclassified as a responder using a method comprising:

a. calculating the percentage (%) of eosinophils in a blood sample takenfrom a COPD patient;

b. determining that the patient is a responder if the percentage ofeosinophils in the blood sample is >2%.

In a further embodiment, the present invention is directed to a methodof reducing the rate of decline in lung function in a patient with COPDcomprising the steps of:

a. calculating the percentage (%) of eosinophils in a blood sample takenfrom a COPD patient;

b. determining that the patient is a responder if the percentage ofeosinophils in the blood sample is >2%;

c. administering a therapeutically effective amount of a pharmaceuticalproduct comprising fluticasone furoate to said patient identified as aresponder.

In a further embodiment, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forreducing the rate of decline in lung function in a patient with COPD,wherein the patient has a blood eosinophil count of >2%.

In a further embodiment, the present invention is directed to the use offluticasone furoate for the manufacture of a pharmaceutical product forreducing the rate of decline in lung function in a patient with COPD,wherein the patient has a blood eosinophil count >2%, and wherein themethod comprises identifying that the patient has a blood eosinophilcount >2% by analysis of a blood sample taken from said patient and thenadministering the pharmaceutical product comprising fluticasone furoateto the patient.

Pharmaceutical products of the present invention may contain fluticasonefuroate as the sole active therapeutic agent. Alternatively,pharmaceutical products of the present invention may comprise one ormore further therapeutic agents in addition to the inhaledcorticosteroid, fluticasone furoate. Further therapeutic agents mayinclude bronchodilators, for example, beta₂-agonists, such as vilanteroltrifenatate; and muscarinic antagonists, such as umeclidinium bromide.In one embodiment, the pharmaceutical product of the present inventionfurther comprises umeclidinium bromide. In another embodiment, thepharmaceutical product further comprises vilanterol trifenatate. In yeta further embodiment, the pharmaceutical product further comprisesvilanterol trifenatate and umeclidinium bromide.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate, umeclidiniumbromide and vilanterol trifenatate for use in the treatment of COPD in apatient, wherein the patient has a blood eosinophil count of ≥150cells/μl, wherein the pharmaceutical product reduces the rate of declinein lung function in a COPD patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate, umeclidiniumbromide and vilanterol trifenatate for use in a method for reducing therate of decline in lung function COPD in a patient, wherein the patienthas a blood eosinophil count of ≥150 cells/μl, and wherein the methodcomprises identifying that the patient has a blood eosinophil count of≥150 cells/μl by analysis of a blood sample taken from said patient andthen administering the pharmaceutical product to the patient.

In a further embodiment, the present invention is directed to apharmaceutical product comprising fluticasone furoate, umeclidiniumbromide and vilanterol trifenatate for use in reducing the rate ofdecline in lung function in a COPD patient classified as a responderusing a method comprising:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils per microlitre of blood in the blood sample is ≥150cells/μl.

In a further embodiment, the present invention is directed to a methodof reducing the rate of decline in lung function in a patient with COPDcomprising the steps of:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils per microlitre of blood in the blood sample is ≥150cells/μl;

c. administering a therapeutically effective amount of a pharmaceuticalproduct comprising fluticasone furoate, umeclidinium bromide andvilanterol trifenatate to said patient identified as a responder.

A pharmaceutical product of the present invention comprising fluticasonefuroate and optionally one or more therapeutic agents, may be anyproduct that is capable of delivering the therapeutic agent(s) by theinhaled route. For example, the pharmaceutical product may be areservoir dry powder inhaler, unit-dose dry powder inhaler, pre-meteredmulti-dose dry powder inhaler, pressurised metered dose inhaler or anebuliser. Furthermore, the pharmaceutical product may be more than oneinhaler where, for example, the pharmaceutical product comprises two ormore therapeutic agents and these are presented as separate compositionsin different inhalers but intended to be used in combination for thetreatment of COPD. A pharmaceutical product that contains two or moretherapeutic agents can, however, be a single inhaler, wherein the two ormore therapeutic agents are formulated in the same composition orpresented in separate compositions within the same inhaler. Separatepresentation within the same inhaler enables therapy to be administeredsequentially or simultaneously.

When the pharmaceutical product of the present invention comprisingfluticasone furoate additionally includes umeclidinium bromide, thisadditional agent may be formulated separately from fluticasone furoateand presented for either sequential or simultaneous administration ormay be admixed with fluticasone furoate and presented in the samecomposition. The same is true for vilanterol trifenatate.

When the pharmaceutical product of the present invention comprisesfluticasone furoate, umeclidinium bromide and vilanterol trifenatate,these three therapeutic agents may be formulated separately andpresented for either sequential or simultaneous administration or theymay be admixed and presented in the same composition. In another option,two therapeutic agents may be admixed and presented in the samecomposition with the third therapeutic agent presented in a secondcomposition. For example, umeclidinium bromide and vilanteroltrifenatate may be admixed together in the same composition withfluticasone furoate presented in a separate composition.

In one embodiment, the pharmaceutical product is a dry powder inhaler.

A dry powder inhaler may include one or more, for example two, drypowder compositions. A dry powder composition will typically include thetherapeutic agent(s) formulated with one or more carriers and/orexcipients, but compositions consisting of just the therapeutic agent(s)are within the ambit of this invention.

Dry powder compositions as described herein may be provided in bulk, inthe reservoir of reservoir-type inhalation devices. Suchreservoir-devices are provided with a metering mechanism for metering adose of the composition from the bulk in the reservoir, and exposing themetered dose in an inhalation channel, where the metered dose is able tobe inhaled by a patient inhaling at a mouthpiece of the device.Exemplary marketed devices of this type are TURBUHALER™ of AstraZeneca,TWISTHALER™ of Schering and CLICKHALER™ of Innovata.

In a further embodiment, a dry powder composition suitable for inhaledadministration may be incorporated into a plurality of sealed dosecontainers provided on medicament pack(s) mounted inside a suitableinhalation device. The containers may be rupturable, peelable orotherwise openable one-at-a-time and the doses of the dry powdercomposition administered by inhalation on a mouthpiece of the inhalationdevice, as known in the art. The medicament pack may take a number ofdifferent forms, for instance a disk-shape or an elongate strip.Representative inhalation devices are the DISKHALER™, DISKUS™ andELLIPTA™ devices, marketed by GSK. The DISKUS™ inhalation device is, forexample, described in GB 2242134A/U.S. Pat. No. 5,873,360.

A further delivery method for a dry powder inhalable composition is formetered doses of the composition to be provided in capsules (one doseper capsule) which are then loaded into an inhalation device, typicallyby the patient on demand. The device has means to rupture, pierce orotherwise open the capsule so that the dose is able to be entrained intothe patient's lung when they inhale at the device mouthpiece. ROTAHALER™of GSK and HANDIHALER™ of Boehringer Ingelheim are examples of suchdevices.

A dry powder composition may also be presented in an inhaled deliverydevice which permits separate containment of therapeutic agentsoptionally in admixture with one or more carriers and/or excipients.Thus, for example, the individual therapeutic agents of thepharmaceutical product of the present invention are administrablesimultaneously but are stored separately, e.g. in separatepharmaceutical compositions, for example as described in WO 2003/061743A1/US2007-0062525, WO 2007/012871 A1/US2008-0196718 and/orWO2007/068896/U.S. Pat. No. 8,534,281. In one embodiment, a deliverydevice permitting separate containment of the therapeutic agents has twomedicament packs in peelable blister strip form, each pack containingpre-metered doses in blister pockets arranged along its length. Saiddevice has an internal indexing mechanism which, each time the device isactuated, peels opens a pocket of each strip and positions the packs sothat each newly exposed dose of each pack is adjacent a manifold whichcommunicates with a mouthpiece of the device. When the patient inhalesat the mouthpiece, each dose is simultaneously drawn out of itsassociated pocket into the manifold and entrained via the mouthpieceinto the patient's respiratory tract. Thus, each time the device isused, the patient is administered a combination therapy consisting of adose from each medicament pack. DUGHALER™ of Innovata and ELLIPTA™ ofGSK permit separate containment of multiple therapeutic agents in thesame inhaler device.

In a further embodiment, the pharmaceutical product is a dry powderinhaler comprising a dry powder composition comprising fluticasonefuroate and a pharmaceutically acceptable carrier.

In a further embodiment, the pharmaceutical product is a dry powderinhaler comprising a first dry powder composition comprising fluticasonefuroate and optionally one or more pharmaceutically acceptable carriersand/or excipients, and a second dry powder composition comprisingumeclidinium bromide and optionally one or more pharmaceuticallyacceptable carriers and/or excipients.

n a further embodiment, the pharmaceutical product is a dry powderinhaler comprising a first dry powder composition comprising fluticasonefuroate and optionally one or more pharmaceutically acceptable carriersand/or excipients, and a second dry powder composition comprisingvilanterol trifenatate and optionally one or more pharmaceuticallyacceptable carriers and/or excipients.

In a further embodiment, the pharmaceutical product is a dry powderinhaler comprising a first dry powder composition comprising fluticasonefuroate and optionally one or more pharmaceutically acceptable carriersand/or excipients, and a second dry powder composition comprisingumeclidinium bromide, vilanterol trifenatate and optionally one or morepharmaceutically acceptable carriers and/or excipients.

Dry powder compositions for delivery via a dry powder inhaler may bepresented in unit dosage form, for example, in capsules, cartridges orblisters made from, for example, laminated aluminium foil. In a furtherembodiment, each unit dose may contain, for example, 50, 100, 200, 250mcg of fluticasone furoate. In a further embodiment, each unit dose maycontain 100 mcg of fluticasone furoate.

If a pharmaceutical product of the present invention additionallycomprises umeclidinium bromide, each unit dose may contain, for example,15.625 mcg, 31.25 mcg, 62.5 mcg or 125 mcg of the free cation. In afurther embodiment, each unit dose may contain 62.5 mcg of umeclidiniumbromide calculated as the amount of free cation rather than the salt.

If a pharmaceutical product of the present invention additionallycomprises vilanterol trifenatate, each unit dose may contain, forexample, 3 mcg, 6.25 mcg, 12.5 mcg, 25 mcg, 50 mcg or 100 mcg of thefree base. In a further embodiment, each unit dose may contain 25 mcg ofvilanterol trifenatate calculated as the amount of free base rather thanthe triphenylacetate salt.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising two dry powder compositions, the first drypowder composition comprising fluticasone furoate in an amount of about100 mcg/dose and the second dry powder composition comprisingumeclidinium bromide in an amount of about 62.5 mcg/dose or 125 mcg/doseand/or vilanterol trifenatate in an amount of about 25 mcg/dose for usein the treatment of COPD in a patient, wherein the patient has a bloodeosinophil count of ≥150 cells/μl, wherein the dry powder inhalerreduces the rate of decline in lung function in a COPD patient.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising a dry powder inhaler comprising two dry powdercompositions, the first dry powder composition comprising fluticasonefuroate in an amount of about 100 mcg/dose and the second dry powdercomposition comprising umeclidinium bromide in an amount of about 62.5mcg/dose or 125 mcg/dose and/or vilanterol trifenatate in an amount ofabout 25 mcg/dose for use in a method for reducing the rate of declinein lung function COPD in a patient, wherein the patient has a bloodeosinophil count of ≥150 cells/μl, and wherein the method comprisesidentifying that the patient has a blood eosinophil count of ≥150cells/μl by analysis of a blood sample taken from said patient and thenadministering the dry powder inhaler to the patient.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising two dry powder compositions, the first drypowder composition comprising fluticasone furoate in an amount of about100 mcg/dose and the second dry powder composition comprisingumeclidinium bromide in an amount of about 62.5 mcg/dose or 125 mcg/doseand/or vilanterol trifenatate in an amount of about 25 mcg/dose for usein reducing the rate of decline in lung function in a COPD patientclassified as a responder using a method comprising:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl.

In a further embodiment, the present invention is directed to a methodof reducing the rate of decline in lung function in a patient with COPDcomprising the steps of:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl;

administering a therapeutically effective amount of a dry powder inhalercomprising two dry powder compositions, the first dry powder compositioncomprising fluticasone furoate in an amount of about 100 mcg/dose andthe second dry powder composition comprising umeclidinium bromide in anamount of about 62.5 mcg/dose or 125 mcg/dose and/or vilanteroltrifenatate in an amount of about 25 mcg/dose to said patient identifiedas a responder.

Dry powder compositions may comprise a carrier. The carrier when it islactose e.g. α-lactose monohydrate, may form from about 91 to about 99%,e.g. 97.7-99.0% or 91.0-99.2% by weight of the formulation. In general,the particle size of the carrier, for example lactose, will be muchgreater than the inhaled therapeutic agents(s) within the dry powdercomposition. When the carrier is lactose it will typically be present asmilled lactose, having a MMD (mass median diameter) of 60-90 μm. Activeingredients, for example fluticasone furoate, for administration byinhalation desirably have a controlled particle size. The optimumparticle size for inhalation into the bronchial system is usually 1-10μm, preferably 2-5 μm. Particles having a size above 20 μm are generallytoo large when inhaled to reach the small airways. To achieve theseparticle sizes the particles of the active ingredient as produced may besize reduced by conventional means e.g. by micronization. The desiredfraction may be separated out by air classification or sieving.Preferably, the particles will be crystalline.

The lactose component may comprise a fine lactose fraction. The ‘fine’lactose fraction is defined as the fraction of lactose having a particlesize of less than 7 μm, such as less than 6 μm, for example less than 5μm. The particle size of the ‘fine’ lactose fraction may be less than4.5 μm. The fine lactose fraction, if present, may comprise 2 to 10% byweight of the total lactose component, such as 3 to 6% by weight finelactose, for example 4.5% by weight fine lactose.

Dry powder compositions may also include, in addition to the activeingredient and carrier, a further excipient (eg a ternary agent) such asa sugar ester, calcium stearate or magnesium stearate. Magnesiumstearate, if present in the composition, is generally used in an amountof about 0.2 to 2%, e.g. 0.6 to 2% or 0.5 to 1.75%, e.g. 0.6%, 0.75%,1%, 1.25% or 1.5% w/w, based on the total weight of the composition. Themagnesium stearate will typically have a particle size in the range 1 to50 μm, and more particularly 1-20 μm, e.g. 1-10 μm. Commercial sourcesof magnesium stearate include Peter Greven, Covidien/Mallinckodt andFACI.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising two dry powder compositions, the first drypowder composition comprising:

a. fluticasone furoate in an amount of about 100 mcg/dose, and

b. lactose;

and the second dry powder composition comprising:

a. umeclidinium bromide in an amount of about 62.5 mcg/dose, and

b. vilanterol trifenatate in an amount of about 25 mcg/dose, and

c. lactose, and

d. magnesium stearate in an amount of about 0.6% w/w;

for use in the treatment of COPD in a patient, wherein the patient has ablood eosinophil count of ≥150 cells/μl, wherein the dry powder inhalerreduces the rate of decline in lung function in a COPD patient.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising two dry powder compositions, the first drypowder composition comprising:

a. fluticasone furoate in an amount of about 100 mcg/dose, and

b. lactose;

and the second dry powder composition comprising:

a. umeclidinium bromide in an amount of about 62.5 mcg/dose, and

b. vilanterol trifenatate in an amount of about 25 mcg/dose, and

c. lactose, and

d. magnesium stearate in an amount of about 0.6% w/w;

for use in a method for reducing the rate of decline in lung functionCOPD in a patient, wherein the patient has a blood eosinophil count of≥150 cells/μl, and wherein the method comprises identifying that thepatient has a blood eosinophil count of ≥150 cells/μl by analysis of ablood sample taken from said patient and then administering the drypowder inhaler to the patient.

In a further embodiment, the present invention is directed to a drypowder inhaler comprising two dry powder compositions, the first drypowder composition comprising:

a. fluticasone furoate in an amount of about 100 mg/dose, and

b. lactose;

and the second dry powder composition comprising:

a. umeclidinium bromide in an amount of about 62.5 mcg/dose, and

b. vilanterol trifenatate in an amount of about 25 mcg/dose, and

c. lactose, and

d. magnesium stearate in an amount of about 0.6% w/w;

for use in reducing the rate of decline in lung function in a COPDpatient classified as a responder using a method comprising:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl.

In a further embodiment, the present invention is directed to a methodof reducing the rate of decline in lung function in a patient with COPDcomprising the steps of:

a. calculating the number of eosinophils per microlitre of blood in ablood sample taken from a COPD patient;

b. determining that the patient is a responder if the number ofeosinophils in the blood sample is ≥150 cells/μl;

administering a therapeutically effective amount of a dry powder inhalercomprising two dry powder compositions, the first dry powder compositioncomprising:

a. fluticasone furoate in an amount of about 100 mcg/dose, and

b. lactose;

and the second dry powder composition comprising:

a. umeclidinium bromide in an amount of about 62.5 mcg/dose, and

b. vilanterol trifenatate in an amount of about 25 mcg/dose, and

c. lactose, and

d. magnesium stearate in an amount of about 0.6% w/w;

to said patient identified as a responder.

EXAMPLE 1 Re-Analysis of Clinical Study Data

Methods: The results of ISOLDE (Burge P S et al BMJ 2000; 320:1297-303), a 3-year study of the effects of fluticasone propionate (FP)500 mcg twice daily on rate of decline of FEV₁ in well-characterisedCOPD patients were re-analysed by baseline blood eosinophil count (≥2%,<2%).Results: The pre-specified analysis of ISOLDE showed no effect of FP onthe rate of decline of FEV₁ for FP vs. placebo. Eosinophil count was <2%in 68% of patients; the spirometric characteristics of these patientswere similar to those with an eosinophil count ≥2%. Patients with aneosinophil count <2% showed no difference in rate of decline of FEV₁with FP vs. placebo (figure). In patients with an eosinophil count ≥2%,FP 500 mcg slowed the rate of decline of lung function by 38 mL per yearcompared with placebo (p=0.001).Conclusion: A baseline blood eosinophil count of 2% identifies a groupof COPD patients who show a slower rate of decline of FEV₁ when treatedwith inhaled corticosteroids.

EXAMPLE 2 Clinical Study

A 52-week, randomised, double-blind, 3-arm parallel group clinical studyis performed to compare the efficacy, safety and tolerability of thefixed dose triple combination FF/UMEC/VI with the fixed dose dualcombinations of FF/VI and UMEC/VI, all given once daily in the morningvia a dry powder inhaler in subjects with COPD.

The treatment groups:

FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg

FF/VI 100 mcg/25 mcg

UMEC/VI 62.5 mcg/25 mcg

The primary objective is to evaluate the efficacy of FF/UMEC/VI toreduce the annual rate of moderate and severe exacerbations comparedwith dual therapy of FF/VI or UMEC/VI in subjects with COPD. A secondaryobjective is to evaluate the efficacy of FF/UMEC/VI to reduceexacerbations compared with UMEC/VI in the subset of subjects with ablood eosinophil count ≥150 cells/μl. An extension of the above study isperformed with the primary objective of assessing the rate of decline inFEV₁ for FF/UMEC/VI versus UMEC/VI in the high eosinophil group (≥150cells/μl).

EXAMPLE 3 Post-Hoc Analysis of Clinical Study Data

Fluticasone furoate (FF)/vilanterol (VI) reduces COPD exacerbations whencompared with treatment with VI alone. Identification of a simplebiomarker would allow targeted treatment. The objective of this post-hocanalysis of clinical study data was to compare exacerbation ratesbetween FF/VI and VI in patients with moderate to very severe COPD,stratified by blood eosinophil level.Methods: We evaluated the use of blood eosinophil count through post-hocanalysis of pooled data from two randomised, double-blind,placebo-controlled 1-year trials (Dransfield M T et al, Lancet Resp Med2013; 1: 210-23) comparing FF/VI (50/25 mcg, 100/25 mcg or 200/25 mcgonce daily) to VI (25 mcg once daily) in patients with COPD and ahistory of exacerbations in the last year. We evaluated the FF-relatedreduction in exacerbation rates in patients with eosinophil counts <2%and ≥2%.Results: 3177 patients provided blood samples at study entry; 2083 (66%)had eosinophils ≥2%. Exacerbation rates were higher in the subgrouptreated with VI alone (1.28 vs 0.91/patient/yr). Baseline eosinophilcount was significantly associated with reduced exacerbation rates withthe three doses of FF/VI combined. Exacerbations were reduced by 29%(p<0.001) in patients with eosinophils ≥2% and 10% (p=0.283) in thosewith <2%. Treatment differential increased with increasing FF dose. Inpatients with eosinophils ≥2% receiving FF/VI 50/25 mcg, 100/25 mcg and200/25 mcg, exacerbations reductions were, respectively: 21%, 33%, 33%(all p<0.01). For eosinophils <2%, the corresponding reductions were 9%,18%, 3%.Conclusion: Blood eosinophil level is a promising biomarker of responsefor inhaled corticosteroid (ICS) treatment in patients with COPD.

1-18. (canceled)
 19. A method of reducing the rate of decline in lungfunction in a human patient with COPD, wherein the patient having COPDhas a blood eosinophil count of ≥150 cells/μL, and further wherein themethod comprises administering to the patient an inhaled pharmaceuticalproduct comprising fluticasone furoate.
 20. The method of claim 19,wherein the inhaled pharmaceutical product comprises a dry powderinhaler, said dry powder inhaler comprising one or more dry powdercompositions.
 21. The method of claim 20, wherein said one or more drypowder-compositions are in unit-dose form.
 22. The method of claim 21,wherein fluticasone furoate is present in an amount of about 100mcg/dose.
 23. The method of claim 22, wherein the inhaled pharmaceuticalproduct further comprises lactose monohydrate.
 24. The method of claim19, wherein the inhaled pharmaceutical product further comprisesumeclidinium bromide.
 25. The method of claim 24, wherein the inhaledpharmaceutical product-comprises a dry powder inhaler, wherein said drypowder inhaler comprises one or more dry powder compositions.
 26. Themethod of claim 25, wherein said one or more dry powder compositions arepresent in unit-dose form.
 27. The method of claim 26, wherein saidfluticasone furoate is present in an amount of about 100 mcg/dose, andsaid umeclidinium bromide is present in an amount of about 62.5 mcg (ofthe free cation)/dose or 125 mcg (of the free cation)/dose.
 28. Themethod of claim 26, wherein said one or more dry powder compositionscomprises a first and a second dry powder composition, each in unit doseform, wherein said first dry powder composition comprises saidfluticasone furoate in an amount of about 100 mcg/dose; and; said seconddry powder composition comprises said umeclidinium bromide in an amountof about 62.5 mcg (of the free cation)/dose or 125 mcg (of the freecation)/dose.
 29. The method of claim 28, wherein said first dry powdercomposition comprises said fluticasone furoate and lactose monohydrate;and said second dry powder composition comprises said umeclidiniumbromide and further comprises lactose monohydrate, and magnesiumstearate.
 30. The method of claim 29, wherein said magnesium stearate ispresent in an amount of 0.6% w/w of said second composition.
 31. Themethod of claim 29, wherein said first and second compositions in unitdose form are presented for simultaneous administration.
 32. The methodof claim 19, wherein the inhaled pharmaceutical product furthercomprises vilanterol trifenatate.
 33. The method of claim 32, whereinthe inhaled pharmaceutical product comprises a dry powder inhaler, saiddry powder inhaler comprising one or more dry powder compositions. 34.The method of claim 33, wherein said one or more dry powder compositionsare present in unit-dose form.
 35. The method of claim 34, wherein saidfluticasone furoate is present in an amount of about 100 mcg/dose andsaid vilanterol trifenatate is present in an amount of about 25 mcg (ofthe free base)/dose.
 36. The method of claim 35, wherein said dry powderinhaler comprises a first and a second dry powder composition, saidfirst dry powder composition comprising said fluticasone furoate in anamount of about 100 mcg/dose, and; said second dry powder compositioncomprising said vilanterol trifenatate in an amount of about 25 mcg (ofthe free base)/dose.
 37. The method of claim 36, wherein said first drypowder composition further comprises lactose monohydrate; and saidsecond dry powder composition further comprises lactose monohydrate andmagnesium stearate.
 38. The method of claim 36, wherein said magnesiumstearate is present in an amount of 0.6% w/w of the second composition.39. The method of claim 36, wherein said first and second dry powdercompositions are in unit dose form and are presented for simultaneousadministration.
 40. The method of claim 19, wherein the inhaledpharmaceutical product further comprises umeclidinium bromide andvilanterol trifenatate.
 41. The method of claim 40, wherein the inhaledpharmaceutical product comprises a dry powder inhaler, wherein said drypowder inhaler comprising one or more dry powder compositions.
 42. Themethod of claim 41, wherein said one or more dry powder compositions arein unit-dose form.
 43. The method of claim 42, wherein said fluticasonefuroate is present in an amount of about 100 mcg/dose, said umeclidiniumbromide is in an amount of about 62.5 mcg (of the free cation)/dose or125 mcg (of the free cation)/dose, and said vilanterol trifenatate is inan amount of about 25 mcg (of the free base)/dose.
 44. The method ofclaim 43, wherein the dry powder inhaler comprises a first and a seconddry powder composition, said first dry powder composition comprisingsaid fluticasone furoate in an amount of about 100 mcg/dose, and; saidsecond dry powder composition comprising said umeclidinium bromide in anamount of about 62.5 mcg (of the free cation)/dose or 125 mcg (of thefree cation)/dose and said vilanterol trifenatate in an amount of about25 mcg (of the free base)/dose.
 45. The method of claim 44, wherein saidfirst dry powder composition further comprises lactose monohydrate; andsaid second dry powder composition further comprises lactose monohydrateand magnesium stearate.
 46. The method of claim 45, wherein saidmagnesium stearate is present in an amount of 0.6% w/w of the secondcomposition.
 47. The method of claim 45, wherein said first and seconddry powder compositions are in unit dose form and are presented forsimultaneous administration.